The present invention relates to a process for synthesizing certain COX-2 inhibiting compounds. Additionally certain intermediate compounds are included.
Cyclooxygenase-2 (COX-2) is an enzyme that is implicated in pain, inflammation, hormone-induced uterine contrations and certain types of cancer growth. Until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1. COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. While the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow, the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will reduce fever, inhibit the inflammatory process, counteract hormone-induced uterine contractions and have potential anti-cancer effects,along with a diminished ability to induce some of the mechanism-based side effects.
One object of the present invention is to provide a synthesis scheme for COX-2 inhibiting compounds which utilizes reduced temperatures in the synthesis.
Another object of the present invention is to utilize a synthetic route that provides high yields.
Another object of the present invention is to provide a synthesis scheme that utilizes a minimum of process steps.
These and other objects will be apparent to those of ordinary skill from the teachings contained herein.